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Can Synthetic Lethality Approach Be Used with DNA Repair Genes for Primary and Secondary MDS?

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Can Synthetic Lethality Approach Be Used with DNA Repair Genes for Primary and Secondary MDS? Medical Oncology (2019) 36:99 https://doi.org/10.1007/s12032-019-1324-7 ORIGINAL PAPER Can synthetic lethality approach be used with DNA repair genes for primary and secondary MDS? Howard Lopes Ribeiro Junior1,2 · Roberta Taiane Germano de Oliveira1,2 · Daniela de Paula Borges1,2 · Marília Braga Costa1,2 · Izabelle Rocha Farias1,2 · Antônio Wesley Araújo dos Santos1,2 · Silvia Maria Meira Magalhães1,2 · Ronald Feitosa Pinheiro1,2,3 Received: 5 August 2019 / Accepted: 15 October 2019 / Published online: 30 October 2019 © Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Cancer-specifc defects in DNA repair pathways create the opportunity to employ synthetic lethality approach. Recently, GEMA (gene expression and mutation analysis) approach detected insufcient expression of BRCA or NHEJ (non-homol- ogous end joining) to predict PARP inhibitors response. We evaluated a possible role of DNA repair pathways using gene expression of single-strand break (XPA, XPC, XPG/ERCC5, CSA/ERCC8, and CSB/ERCC6) and double-strand break (ATM, BRCA1, BRCA2, RAD51, XRCC5, XRCC6, LIG4) in 92 patients with myelodysplastic syndrome (73 de novo, 9 therapy- related (t-MDS). Therapy-related MDS (t-MDS) demonstrated a signifcant downregulation of axis BRCA1-BRCA2-RAD51 comparing to normal controls (p = 0.048, p = 0.001, p = 0.001). XRCC6 showed signifcantly low expression in de novo MDS comparing to controls (p = 0.039) and for patients who presented chromosomal abnormalities (p = 0.047). Downregula- tion of LIG4 was consistently associated with poor prognostic markers in de novo MDS (hemoglobin < 8 g/dL (p = 0.040), neutrophils < 800/mm3 (p < 0.001), patients with excess of blasts (p = 0.001), very high (p = 0.002)/high IPSS-R (p = 0.043) and AML transformation (p < 0.001). We also performed an evaluation of GEPIA Database in 30 cancer types and detected a typical pattern of downregulation as here presented in primary or secondary MDS. All these results suggest synthetic lethality approach can be tested with DNA repair genes (beyond that of BRCA1/2 status) for de novo and therapy-related myelodysplastic syndrome and may encourage clinical trials evaluating the use of PARP1 inhibitors in MDS. Howard Lopes Ribeiro Junior and Roberta Taiane Germano de Oliveira have equal credits. Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1203 2-019-1324-7) contains supplementary material, which is available to authorized users. * Ronald Feitosa Pinheiro Silvia Maria Meira Magalhães [email protected]; [email protected] [email protected] Howard Lopes Ribeiro Junior 1 Cancer Cytogenomic Laboratory, Center for Research [email protected] and Drug Development (NPDM), Federal University Roberta Taiane Germano de Oliveira of Ceara, 1000 Coronel, Nunes de Melo St. Rodolfo Teóflo, [email protected] Fortaleza, Ceara 60430-275, Brazil Daniela de Paula Borges 2 Post-Graduate Program in Medical Science, Federal [email protected] University of Ceara, Fortaleza, Ceara, Brazil Marília Braga Costa 3 Post-Graduate Program of Pathology, Federal University [email protected] of Ceara, Fortaleza, Ceara, Brazil Izabelle Rocha Farias [email protected] Vol.:(0123456789)1 3 99 Page 2 of 10 Medical Oncology (2019) 36:99 Graphic Abstract Keywords Myelodysplastic syndrome · Synthetic lethality · DNA repair · Gene expression Introduction Nucleotide excision repair (NER) is the main pathway used by mammals to restore SSB of DNA, removing bulky Primary (or de novo) myelodysplastic syndrome (MDS) is DNA lesions done by environmental mutagens, cancer a hematopoietic stem-cell (HSCs) disorder characterized by chemotherapeutic adducts and UV light [10, 11]. The two bone marrow failure related to aging with increased risk of main branches of NER pathway are the global genome acute myeloid leukemia (AML) transformation [1]. Second- repair (GGR), probing the genome for strand distortions, ary or therapy-related myelodysplastic syndrome (t-MDS) is and the transcription-coupled repair (TCR) that removes a subcategory of therapy-related myeloid neoplasms (t-MNs) distorting lesions that block elongating RNA polymerases. derived from cytotoxic therapies (i.e. chemotherapy and/ Genes of Xeroderma pigmentosum group, especially XPA, or radiotherapy) characterized by complex chromosomal XPC, XPD, XPG [11, 12] and Cockayne syndrome genes, abnormalities and higher risk of progression to AML than especially CSA/ERCC8 and CSB/ERCC6, are essential to de novo MDS [2, 3]. Chemotherapy and radiotherapy induce NER properly function [13, 14]. For both branches of NER DNA lesions in single or double-strands of DNA, predispos- (CGR and TCR), XPA, XPF and XPG/ERCC5 are reported ing to chromosomal rearrangements, amplifcations, dele- as truly efectors. tions, overall genomic instability and cancer development The three main pathways involved in DSBs repair are [3, 4]. homologous recombination (HR), non-homologous end Genomic instability is the hallmark of cancer [5] and joining (NHEJ) [5, 16] and single-strand annealing (SSA) patients with MDS present chromosomal abnormalities and [17]. HR, an error-free system, uses a sister chromatid in mutations in up to 94% of cases [1, 6]. Epidemiologic evi- the formation of heteroduplex [5, 18]. The main proteins dence has suggested up to two-thirds of mutations in cancer are BRCA1 and BRCA2 which interact with recombi- are caused by errors during DNA replication, reinforcing the nase RAD51 to follow the role repair [5, 18]. The NHEJ importance of DNA repair system [7]. For the maintenance mechanism, an error-prone repair, has as main components and protection of genome integrity, cells have molecular Ku80/XRCC5, Ku70/XRCC6 and LIG4. Ku80 and Ku70, DNA repair pathways to restore single (SSB) and double- encoded by XRCC5 and XRCC6 genes, respectively, bind strand (DSBs) breaks of DNA [5]. These breaks have been the DNA ends while LIG4 performs rearrangement, join- associated with chromosomal abnormalities, the most sig- ing the two end-junctions of DNA strands breaks [5, 9, nifcant marker of prognosis for MDS [8, 9]. 19]. 1 3 Medical Oncology (2019) 36:99 Page 3 of 10 99 Identifcation of specifc DNA repair pathway defect Table 1 Clinical and laboratory characteristics of de novo MDS can facilitate a precision oncology approach, increasing the patients chance of cure and better therapy selection [20]. Cancer- Variables N % specifc defects in DNA repair pathways create the oppor- tunity to employ synthetic lethality, which has been applied Age (in years) ≤ 60 26 35.6 against cancer cells harboring mutations in BRCA1 and > 60–70 17 23.3 BRCA2 using PARP1 inhibitors (PARPi) [20]. The aim of > 70–80 19 26.0 this report is to evaluate a possible role of specifc defects ≥ 80 11 15.1 related to DNA repair pathways (single (SSB) and double- Gender Male 35 47.9 strand (DSBs) breaks of DNA) in de novo and therapy- Female 38 52.1 related MDS, trying to identify possible targets to synthetic Origin Urban 44 62.9 lethality approach. Rural 26 37.1 Fibrosis Absence 9 47.4 Presence 10 52.6 Materials and methods Nº of dysplasias (BM) 1 12 29.3 2 21 51.2 Patients 3 8 19.5 Dyserythropoiesis Yes 32 78.0 Eighty-two patients with MDS (Seventy-three de novo and No 9 22.0 nine therapy-related MDS patients) were diagnosed at Fed- Dysmegakaryopoiesis Yes 17 41.5 eral University of Ceara (UFC)/Center for Research and No 24 58.5 Drug Development (NPDM) according to WHO 2016. Pri- Dysgranulopoiesis Yes 29 70.7 mary MDS patients were evaluated according to Revised No 12 29.3 International Prognostic Scoring System (IPSS-R). See Micromegakaryocyte Yes 10 21.7 Table 1. Ten bone marrow samples from healthy volunteers No 36 78.3 were used as controls. This study was approved by the Eth- Ring sideroblasts (%) ≥ 1– < 15% 5 22.7 ics Committee of UFC (#1.292.509). Informed consent was > 15– < 50% 6 27.3 ≥ 50% 11 50.0 obtained from all patients and controls. Blasts count (%) ≤ 5% 60 82.2 Cytogenetic analysis > 5%– ≤ 10% 5 6.8 > 10% 8 11.0 Cytogenetic Normal 29 56.9 Conventional G-banding karyotype of mononuclear bone Abnormal 22 43.1 marrow cells of all patients was performed as previously Number of clonal alterations Normal 29 56.9 reported [21]. Briefy, cultures were established in RPMI 1 14 27.5 1640 medium (Gibco, Grand Island, NY, USA) containing 2 4 7.8 30% fetal calf serum. For the 24-h culture, colcemid was 3 or more 4 7.8 added at a fnal concentration of 0.05 μg/mL for the fnal IPSS-R cytogenetic risk group Very good 1 2.0 30 min of culture. After harvesting, the cells were exposed Good 38 74.5 to a hypotonic KCl solution (0.068 mol/L) and fxed with Intermediate 9 17.6 Carnoy bufer fxative (acetic acid/methanol in a 1:3 propor- Poor 0 0.0 tion). The slides were prepared and stained using Giemsa Very poor 3 5.9 solution. Twenty metaphases were analyzed whenever pos- Hemoglobin (g/dL) ≥ 10 17 23.3 sible. The karyotype was prepared using CytoVision Auto- ≥ 8– < 10 20 27.4 mated Karyotyping System (Applied Imaging, San Jose, CA, < 8 36 49.3 USA) and described according to the International System ANC (× 10L−1) ≥ 800 48 65.8 for Human Cytogenetic Nomenclature 2016 [22]. < 800 25 34.2 3 Total RNA extraction Platelet (mm ) ≥ 100.000 35 47.9 ≥ 50.000– < 100.000 16 21.9 < 50.000 22 30.1 The bone marrow mononuclear cells were separated after Nº of cytopenias 1 39 53.4 lysis of red cells. Total RNA extractions from isolated mono- 2 18 24.7 nuclear cells (bone marrow), obtained from MDS patients, 3 16 21.9 were performed with TRizol Reagent™ (Invitrogen, 1 3 99 Page 4 of 10 Medical Oncology (2019) 36:99 Table 1 (continued) CA, USA) were used to quantify mRNA expression.
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